Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

Li, Da Qiang; Pakala, Suresh B.; Reddy, Sirigiri Divijendra Natha; Peng, Shaohua; Balasenthil, Seetharaman; Deng, Chu Xia; Lee, Cheng‐Chi; Rea, Michael A.; Kumar, Rakesh

doi:10.1038/ncomms3545

Cited by 16 publications

(10 citation statements)

References 60 publications

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“…6C). Metastasis-associated Protein 1 (MTA1) is known to be upregulated in many cancer types and is an important metastatic marker for tumor aggressiveness and metastasis (34,35). Interestingly, we observed a decreased expression of MTA1 in ORM treated xenograft tissues as compared to control.…”

Section: Resultsmentioning

confidence: 99%

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

Hafeez

Ganju

Sikander

et al. 2017

Molecular Cancer Therapeutics

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Ormeloxifene (ORM), is a clinically approved selective estrogen receptor modulator, which has also shown excellent anti-cancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ORM on prostate cancer (PrCa) and elucidate a novel molecular mechanism of its anti-cancer activity. ORM treatment inhibited epithelial to mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, and vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ORM showed proficient docking with β-catenin and GSK3β. In addition, ORM induced apoptosis, inhibited growth and metastatic potential of PrCa cells and arrested cell cycle in G0-G1 phase via modulation of cell cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ORM remarkably reduced tumorigenic, migratory and invasive potential of PrCa cells. Additionally, ORM treatment significantly (P<0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intra-peritoneal route (250 μg/mouse; thrice weekly). These molecular effects of ORM were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ORM as an anti-cancer drug for the treatment of advanced stage metastatic PrCa through a novel molecular mechanism involving β-catenin and EMT pathway.

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Section: Resultsmentioning

confidence: 99%

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

Hafeez

Ganju

Sikander

et al. 2017

Molecular Cancer Therapeutics

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“…Other coregulators have been described to play a role in circadian rhythm as well, including NCoR with HDAC3, PGC1-α, RIP140, JARID1a, MAP1a, TRAP150, and several others that influence the activities of both NRs and BMAL1:CLOCK (Curtis et al, 2004; DiTacchio et al, 2011; Feng et al, 2011; Lande-Diner et al, 2013; Li et al, 2013; Liu et al, 2007; Poliandri et al, 2011). We believe that the ability of SRC-2 to positively regulate circadian gene expression is largely achieved by coactivation of BMAL1:CLOCK and by SRC-2 targeting its own promoter, possibly to strengthen gene expression in a feed-forward loop.…”

Section: Discussionmentioning

confidence: 99%

SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

et al. 2014

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SUMMARY Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1: CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circa-dian clock.

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“…The SP1 transcription factor stimulates the transcription of MTA1 (Li et al, 2011) as well as of MTA2 (Xia and Zhang, 2001; Zhou et al, 2013) and MTA3 (Fujita et al, 2004a; Fujita et al, 2004a). The expression of MTA1 is also induced by CUTL1 homeodomain in TGF-p1 stimulated (Pakala et al, 2011), NF- κB transcription factor in stress-exposed tumor cells (Pakala et al, 2010), heat shock factor 1-dependent manner (Khaleque et al, 2008), hypoxia inducible factor 1α in breast cancer cells (Yoo et al, 2006), Clock/BMAL1 binding to E-box in murine Mta1 promoter (Li et al 2013a). The estrogen and estrogen receptor-α system stimulates MTA1 expression in endometrial cancer cells (Kong et al, 2014) and MTA3 in breast cancer cells (Fujita et al, 2003; Fujita et al, 2004b; Mishra et al, 2004).…”

Section: Regulation Of Expression Of Mta Genesmentioning

confidence: 99%

Structure, expression and functions of MTA genes

Kumar

Wang

2016

Gene

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Metastatic associated proteins (MTA) are integrators of upstream regulatory signals with the ability to act as master coregulators for modifying gene transcriptional activity. The MTA family includes three genes and multiple alternatively spliced variants. The MTA proteins neither have their own enzymatic activity nor have been shown to directly interact with DNA. However, MTA proteins interact with a variety of chromatin remodeling factors and complexes with enzymatic activities for modulating the plasticity of nucleosomes, leading to the repression or derepression of target genes or other extra-nuclear and nucleosome remodeling and histone deacetylase (NuRD)-complex independent activities. The functions of MTA family members are driven by the steady state levels and subcellular localization of MTA proteins, the dynamic nature of modifying signals and enzymes, the structural features and post-translational modification of protein domains, interactions with binding proteins, and the nature of the engaged and resulting features of nucleosomes in the proximity of target genes. In general, MTA1 and MTA2 are the most upregulated genes in human cancer and correlate well with aggressive phenotypes, therapeutic resistance, poor prognosis and ultimately, unfavorable survival of cancer patients. Here we will discuss the structure, expression and functions of the MTA family of genes in the context of cancer cells.

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Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

Cited by 16 publications

References 60 publications

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

Structure, expression and functions of MTA genes

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